1. Field of the Invention
This invention concerns certain novel platinum complexes having antineoplastic activity. More explicitly, it relates to novel antitumor platinum complexes of 1,2-diaminocyclohexane, 2,2'-bipiperidyl, 1,2-diamino-2,4-dimethylpentane, 1,2-diaminocyclooctane, 3,4-diamino-2,5-dimethylhexane, and 1-aminomethylcyclooctylamine and a variety of more labile ligands.
2. Description of the Prior Art
Rosenberg et al first reported that certain platinum complexes possess antitumor activity against a variety of murine malignancies [B. Rosenberg, L. Van Camp, J. E. Trosko, and V. H. Mansour. Platinum Compounds: A New Class of Potent Antitumor Agents. Nature 222:385-386, 1969]. Hill et al first utilized the platinum complex, cis-dichlorodiammine platinum(II), cisplatin, for the treatment of human cancer patients [J. M. Hill, E. Loeb, R. J. Speer, A. MacLellan, and N. O. Hill. cis-Platinous Diammino Dichloride (PDD) Therapy of Various Malignant Diseases. Proc. Am. Assoc. Cancer Res. 13:20, 1972]. A very informative survey of platinum complexes as antitumor agents was provided by Cleare and Hoeschele [M. J. Cleare and J. D. Hoeschele. Studies on the Antitumor Activity of Group VIII Transition Metal Complexes. Part I. Platinum(II) Complexes. Bioinorg. Chem. 2:187-210, 1973]. These authors were the first to make and test complexes of 1,2-diaminocyclohexane as well as a variety of more labile ligands, especially mono- and di-carboxylates. Connors et al [T. A. Connors, M. Jones, W. C. Ross, P. D. Braddock, A. R. Kohkhar, and M. L. Tobe. New Platinum Complexes with Antitumor Activity. Chem.-Biol. Interact. 5:415-424, 1972], and Hall et al [Larry M. Hall, Robert J. Speer, Helen J. Ridgway, and S. J. Norton. Unsymmetrical C-Substituted Ethylenediamine Platinum Coordination Complexes: Synthesis and Activity Against Mouse Leukemia L1210. J. Inorg. Biochem. 11:139-149, 1979] have also contributed to our understanding of the value of alicyclic diamines in the preparation of platinum antitumor complexes. Other literature of significance includes: [Paul Schwartz, Sandra J. Meischen, Glen R. Gale, Loretta M. Atkins, Alayne B. Smith, and Ernest M. Walker, Jr. Preparation and Antitumor Evaluation of Water-Soluble Derivatives of Dichloro(1,2-Diaminocyclohexane) Platinum(II). Cancer Treatment Reports 61 (8): 1519-1525, 1977], [U.S. Pat. No. 4,169,846], [Yoshinori Kidani and Kenji Inagaki. Antitumor Activity of 1,2-Diaminocyclohexane-Platinum Complexes Against Sarcoma-180 Ascites Form. J. Med. Chem. 21(12):1315-1318, 1978], [Larry M. Hall, Robert J. Speer, Helen J. Ridgway, David P. Stewart, Andrew D. Newman, and Joseph M. Hill. Analogs of Sulfato 1,2-Diaminocyclohexane Platinum(II) (SHP) II. Modifications Other Than Leaving Ligand. J. Clin. Hematol. Oncol. 7(1):231-240,1977], [U.K. Patent Application No. 2,003,468A], [Helen J. Ridgway, Robert J. Speer, Larry M. Hall, David P. Stewart, Andrew D. Newman, and Joseph M. Hill. Analogs of Sulfato 1,2-Diaminocyclohexane Platinum(II). I. Modifications in Leaving Ligand. J. Clin. Hematol. Oncol. 7(1):220-228, 1977], [Yoshinori Kidani, Kenji Inagaki, and Shigeru Tsukagoshi. Examination of Antitumor Activities of Platinum Complexes of 1,2-Diaminocyclohexane Isomers and Their Related Complexes. Gann 67:921-922, 1976], [Robert J. Speer, Larry M. Hall, David P. Stewart, Helen J. Ridgway, Joseph M. Hill, and Yoshinori Kidani. Antitumor Activity of Platinum Complexes of 1,2-Diaminocyclohexane Isomers. J. Clin. Hematol. Oncol. 8(2):44-50, 1978], [D. P. Stewart, R. J. Speer, H. J. Ridgway, and J. M. Hill. Antitumor Activity of Platinum Complexes of trans-3,4-Diamino-2,5-Dimethylhexane Against Mouse Leukemia L1210. J. Clin. Hematol. Oncol. 9(1):174,1979], [Glen R. Gale, Alayne B. Smith, and Paul Schwartz. Preliminary Studies of 4-Carboxyphthalato (1,2-Diaminocyclohexane) Platinum(II): Antitumor Activity and Effects on Macromolecular Synthesis. J. Clin. Hematol. Oncol. 9(3):217-234, 1979], [U.S. Pat. No. 4,115,418], [U.S. Pat. No. 4,256,652], [U.S. Pat. No. 4,284,579], [U.S. Pat. No. 4,359,425], [European Patent Application No. 55,300], [U.K. Patent Application No. 2,093,845], [U.K. Patent Application No. 2,024,823A], and others.
It is evident from the above that a large number of platinum complexes has been reported as having some antitumor activity; however, there remains a need for new platinum antineoplastic complexes which have more advantageous properties, e.g., greater solubility in intravenous fluids, improved stability when dissolved in intravenous fluids, greater antitumor potency, broader spectrum of activity against human malignancies, and less toxicity to patient's kidney, inner ear, gut, bone marrow, etc. It is especially desirable that such new antitumor platinum complexes possess significant advantages over cisplatin, the only platinum complex presently being marketed as an anticancer agent.